5H-{8 1{9 benzopyrano{8 3,4-d{9 pyridines

ABSTRACT

X is a straight or branched chain alkylene group having from 1 to 8 carbon atoms, and wherein R7 and R8 are the same or different members of the group consisting of hydrogen or loweralkyl, or 5H-(1)Benzopyrano(3,4-d)pyridines represented by the formula   WHEREIN EACH R1 is loweralkyl, R2 is alkyl, cycloalkyl or   WHEREIN Y is a straight or branched chain alkylene group having from 1 to 10 carbon atoms and each R4, R5 and R6 are the same or different members of the group consisting of hydrogen, halo, trifluoromethyl or loweralkyl; and R3 is hydroxy, acyloxy or   D R A W I N G WHEREIN X is a straight or branched chain alkylene group having from 1 to 8 carbon atoms, a is an integer from 1 to 4, b is an integer from 1 to 4, Z is CH2, O, S or NR10 with R10 being hydrogen or loweralkyl, with the limitation that when Z is O or S, the sum of a and b is 3 or 4; and when Z is NR10, the sum of a and b is 3-5; R9 is hydrogen or loweralkyl, and the pharmaceutically acceptable salts thereof.

United States Patent [191 Lee [4 1 Apr. 15, 19755H-[1]BENZOPYRANO[3,4-D1PYRIDINES [75] lnventor: Cheuk Man Lee,Waukegan, Ill.

[73] Assignee: Abbott Laboratories, North Chicago, Ill.

22 Filed: July 13,1973

21 Appl. No.: 379,016

[52] U.S. Cl. 260/295 T; 260/297 T; 424/263;

424/266 [51] Int. Cl C07d 31/34 [58] Field of Search 260/295 T, 297 T[56] References Cited UNITED STATES PATENTS 3,635,993 l/l972 Pars et a].260/297 T Primary Examiner-Alan L. Rotman Attorney, Agent, or FirmRobertL. Niblack', Joyce R. Krei; Vincent A. Mallare [57] ABSTRACT5l-l-[1]Benzopyrano[3,4-d]pyridines represented by the formula whereineach R is loweralkyl, R is alkyl, cycloalkyl wherein Y is a straight orbranched chain alkylene group having from 1 to 10 carbon atoms and eachR R and R are the same or different members of the group consisting ofhydrogen, halo, trifluoromethyl or loweralkyl; and R is hydroxy, acyloxyor X is a straight or branched chain alkylene group having from 1 to 8carbon atoms, and wherein R and R are the same or different members ofthe group consisting of hydrogen or loweralkyl, or

\/ (CH2) l) J wherein X is a straight or branched chain alkylene 3Claims, No Drawings SH-[HBENZOPYRANOB,4-D]PYRIDINES DETAILED DESCRIPTIONOF THE INVENTION This invention relates to novel benzopyrans and moreparticularly relates to H-[ 1 ]benzopyrano[3,4- dlpyridines representedby the formula wherein each R is loweralkyl, R is alkyl, cycloalkyl orwherein Y is a straight or branched chain alkylene group having from Ito carbon atoms and each R R and R are the same or different members ofthe group consisting of hydrogen, halo, trifluoromethyl or loweralkyl;and R is hydroxy, acyloxy or ll -oc-x-u Wherein X is a straight orbranched chain alkylene group having from I to 8 carbon atoms, and R andR are the same or different members of the group consisting of hydrogenor loweralkyl, or

As used herein, the term loweralkyl" refers to C -C straight or branchedchain alkyl groups including methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl. neo-pentyl,n-hexyl and the like.

The term "alkyl" refers to straight and branched chain alkyl radicalshaving from I to 20 carbon atoms such as methyl, n-amyl,3-methyl-2-octyl, 2-nonyl, 2- eicosanyl and the like.

Cycloalkyl, as used herein, refers to cyclic saturated aliphaticradicals having 3 to 8 carbon atoms in a ring, such as cyclopropyl,,cyclobutyl, cyclopentyl. cyclohexyl, cycloheptyl and cyclooctyl.

The term halo" includes chloro, fluoro, bromo and iodo.

The term acyloxy" refers to acetoxy, propionyloxy, butyryloxy and thelike.

When R is an ester, the term pharmaceutically acceptable salts refers toacid addition salts prepared by reacting the basic esters of thebenzopyrans with an organic or inorganic acid, or by reacting thebenzopyrans with the salt of an appropriate acid. When R is hydroxy, theterm refers to alkali metal, alkaline earth metal, ammonium andsubstituted ammonium salts such as hydrochloride, hydrobromide, sulfate,bisulfate, acetate, valerate, oleate, laurate, borate, benzoate,lactate, phosphate, tosylate, citrate, maleate, succinate, tartrate,napsylate and the like.

When R is hydroxy, the compounds of this invention are prepared bydehydrogenation of-the corresponding l,2,3.4-tetrahydro-5I-I[ l]benzopyrano[3,4-d]pyridine with, for example, palladium on carbon in aboiling inert solvent, or by debenzylation and dehydrogenation of thecorresponding N-benzyl l,2,3,4-tetrahydro compound. When R is hydroxy,and R is alkyl or cycloalkyl, the tetrahydro compounds can be preparedaccording to the method described in US. Pat. No. 3,576,798. When R ishydroxy, and R is the compounds are prepared according to the followingreaction scheme:

RBI 3 -Y 0CH IIOAc R 0 R H, loweralkyl R-ll or halo RGY R OH .HCl Q coocn CH MgBr 3 R1 6 l I OH Y R Q Compounds wherein R is acyloxy areprepared by reacting the corresponding compound wherein R is hydroxywith the appropriate acyl anhydride such as acetic anhydride.

The esters of this invention, R

are prepared by reacting equimolar quantities of the correspondingbenzopyranopyridine, and the appropriate acid or its salt, in thepresence of a carbodiimide such as dicyclohexyl carbodiimide, in asuitable solvent such as methylene chloride, chloroform and the like.

Some of the heterocyclic acids which can be used in the process are:

'y-piperidinobutyric acid,

y-morpholinobutyric acid,

'y-( Z-methylpiperidino)-butyric acid,

fi-piperidinovaleric acid,

'y-pyrrolidinobutyric acid,

B-piperidinopropionic acid,

'y-thiomorpholinobutyric acid and homopiperidinoacetic acid Reactionbetween the benzopyranopyridine starting material and the heterocyclicacid, or salt thereof, is readily effected by combining about equimolaramounts of the reactants and a slight excess of a carbodiimide such asdicyclohexylcarbodiimide. The reaction proceeds readily at roomtemperature and is generally completed in about 4 to hours. After thereaction is terminated, the reaction mixture can be filtered to removethe by-product of dicyclohexylurea, and the solvent can be distilled offusing a rotary evaporator. The residue can be directly crystallized froma suitable solvent such as benzene/ether or the residue can bechromatographed and the desired material isolated from the appropriatechromatographic fractions. If the basic esters are obtained, the acidaddition salts such as those named above, if desired, can be prepared bymethods well known in the art.

The compounds of this invention, in the form of the free bases, can beused as neutralizing agents since they form salts with acids.

The pharmacological activity of the compounds of this invention rendersthem useful as drugs although it should be understood that everycompound of the invention will not necessarily have each activitypossessed by the others.

The compounds of this invention are useful as analgesic agents, andgenerally at dosages of from 1 to 10 mg./kg. of body weight daily. Theanalgesic activity was established in the standard mouse writhing test[Whittle, Brit. J. P/zarmacoL, 22, 296 1964)] and confirmed in the hotplate assay [Woolfe, G. and MacDonald, A. D., J. P/zarmacol. Exper.T/1erap., 80, 300, [944)] and the rat tail flick test [DAmour and Smith.J. Pharmacol. Exper. T/1erap., 72: 74, (1941)]. The compounds areadditionally useful as anti-anxiety agents and anti-depressant agents.

The following examples further illustrate this invention:

EXAMPLE I 5 ,S-Dimethyll 0-hydroxy-8-( 3-methyl-2-octyl )-5H- l]benzopyrano[3,4-dlpyridine CHCH (CH CH3 EXAMPLE 2 EXAMPLE 3 EXAMPLE 55,5-Dimethyl-lO-hydroxy-8-(l-cyclohexylethyl)-5l-lll]benzopyrano[3,4-dlpyridine is prepared bydehydrogenating 5,5-dimethyll -hydroxy -8-( lcyclohexylethyl 23,4-tetrahydro-H- ll]benzopyrano[3,4-d1pyridine following the procedureof Example 1.

EXAMPLE 6 5.5-Dimethyl-l0-hydroxy-8-(3-cyclopropyl-2-propyl)-5H-[[]benzopyrano[3,4-dlpyridine is prepared by dehydrogenating5,5-dimethyl-l0-hydroxy-8- 3-.cyclopropyl-2-propyl l .2,3,4-tetrahydro-5H- [l]beniopyrano[3,4-d]pyridine following the procedure of Example 1.

EXAMPLE 7 1 5.5-Dimethyl l0-hydroxy-8-92-tetradecyl)-5H-[1]benzopyrano[-(-d]pyridine is prepared by dehydrogenating 5 ,5-dimethyl- 1 O-hydroxy-S-(2-tetradecy1)- l,2,3,4-tetrahydro-5 H-[ l]benzopyrano[ 3,4-d]pyridine following the procedure of Example 1.

EXAMPLE 8 5,5-Dimethyl-l0-hydroxy-8-(2-eicosyl)-5H-[l]benzopyrano[3,4-d]pyridine is prepared by dehydrogenating5,5-dimethyl-l0-hydroxy-8-(2-eicosyl)- l,2,3,4-tetrahydro-5l-l-[ 1benzopyrano[ 3 ,4-dlpyridine following the procedure of Example 1.

EXAMPLE 9 5,5-Dimethyl-l0 hydroxy-8-ethyl-5l-l-[l]benzopyrano[3,4-d1pyridine is prepared by dehydrogenating5,5-dimethyl-l0-hydroxy-8-ethyl-l,2,3,4- tetrahydro-5H-[ l]benzopyrano[3,4-d]pyridine; following the procedure of Example 1.

EXAMPLE 10 5,5-Dimethyl-lO-hydroxy-8-iso-propyl-5H-[l]benzopyranol3,4-d]pyridine is prepared by dehydroge'nating 5,S-dimethyll O-hydroxy-8-iso-propyl- 1,2 ,3 ,4-tetrahydro-5H-[ l]benzopyrano[ 3 ,4-d ]pyridine following the procedure of Example l. Y

EXAMPLE 1 l 5 .S-Dimethyll 0-hydroxy-8-( 2-hexyl )-5 H-[l]benzopyrano[3.4-dlpyridine is prepared by dehydrogenating.5.,5-dimethyl-l0-hydroxy-8-(2-hexyl)- l,2.3.4-tetrahydro-5H-[l]benzopyrano[3,4-d1pyridine following the procedure of Example 1.

EXAMPLE 12 IO-Acetoxy-S ,5-dimethyl-8-( 3-methyl-2-octyl )-5 H l l]benzopyrano[ 3,4-d]pyridine.

ococn r ('JHClKCH on CH A mixture of 3.53 g. 0.01 mole) of5,5-dimethyl-l0- hydroxy-8-(3-methyl-2-octyl)-5H-[ 1]benzopyrano[3,4-d]-pyridine, 1.22 g. (0.012 mole) of acetic anhydride,and 5 ml. of pyridine was stirred at room temperature for 24 hours. Thereaction mixture was evaporated in vacuo. andthe residue was taken up inether. The ether solution was washed with water. dried .with anhydroussodium sulfate, and evaporated in vacuoQ The residue was purified bychromatography on a Florosil activated aluminum magnesium silicate 22 mmX 30 inches column with chloroform to give the pure product. A

Calcd. for C H NO C, 75.91; H, 8.41; N, 3.54.

Foundz-C. 75.62; H, 8.52; N, 3.38.

EXAMPLE l3 lO-Acetoxy-S,5-dimethyl-8-ethyl-5H-[ 1]benzopyrano-[3.4-d]pyridine is prepared by reacting 5,5-dimethyll0-hydroxy-8-ethyl-5H-[ l ]benzopyrano[ 3,4- dlpyridine andacetic anhydride in the presence of pyridine according to the method ofExample l2.

EXAMPLE l4 lOAcetoxy-S,5-dimethyl-8-n-pentyl-5H-l]benzopyrano[3,4-d]pyridine is prepared by reacting5,5-dimethyl-l0-hydroxy-8-n-pentyl-5H- l ]benzopyrano[3,4-d1pyridine andacetic anhydride in the presence of pyridine according to the method ofExample 12 EXAMPLE l5 l0-Acetoxy15.5-dimethyl-8-(2-heptyl)-5H-l]benzopyrano[ 3,4-d] pyridine is prepared by reacting 5 ,S-dimethyll0-hydroxy-8-( 2-heptyl )-5 H- [l]benzopyrano[3,4-d]pyridine and aceticanhydride in the presence of pyridine according to. the method ofExample 12.

EXAMPLE l6 lO-Acetoxy-S,5-dimethyl-8-( l-cyclohexylethyl )-5H-[l]-benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyll0-hydroxy-8-( l-cyclohexylethyl 5H-[l]benzopyrano[ 3,4-d]-pyridine andacetic anhydride in the presence of pyridine according to the method ofExample '12. t I

EXAMPLE 17 l O-Acetoxy-S ,5-dimethyl-8-( 3-cyclopropyl-2-propyl)-5H-[l]benzopyrano[3,4-dlpyridine is prepared by reacting5.5-dimethyl-l-hydroxy-8-(3- cyclopropyl-Z-propyl )-H-[ l]benzopyrano[3.4- d]pyridine and acetic anhydride in the presence ofpyridine according to the method of Example 12.

EXAMPLE l8 l0-Acetoxy-5.5-dimethyl-8-( 2-tetradecyl)-5H-[ 1benzopyrano[3.4-dlpyridine is prepared by reacting5,5-dimethyl-l0-hydroxy-8-(Z-tetradecyl )-5H-[ 1]benzopyrano[3.4-d]-pyridine and acetic anhydride in the presence ofpyridine according to the method of Example l2.

EXAMPLE l9 lO-Acetoxy-S.5-dimethyl-8-(2-eicosyl)-5H- l]benzopyrano[3,4-dlpyridine is prepared by reacting5.5-dimethyl-l0-hydroxy-8-(2-eicosyl)-5H- l ]benzopyrano[3,4-d1pyridineand acetic anhydride in the presence of pyridine according to the methodof Example 12 EXAMPLE 2O lO-Acetoxy-S.5-dimethyl-8-n-butyl-5H-[ 1]benzopyrano-[3.4-d]pyridine is prepared by reacting 5.5- dimethyllO-hydroxy-S-n-butyl-SH- [llbenzopyranol3,4-d1pyridine and aceticanhydride in the presence of pyridine according to the method of Examplel2.

EXAMPLE 21 l0-Acetoxy-5.S-dimethyl-8-iso-propyl-5H- llbenzopyranol3.4-dlpyridine is prepared by reacting5.5-dimethyl-lO-hydroxy-8-iso propyl-5H- l ]benzopyrano[3,4-d1pyridineand acetic anhydride in the presence of pyridine according to the methodof Example 12.

EXAMPLE 22 lO-Acetoxy-S.5-dimethyl-8-(2-hexyl)-5H- l lbenzopyranol 3,4-dIpyridine is prepared by reacting5.5-dimethyl-l0-hydroxy-8-(2-hexyl)-5H- [l]benzopyrano[3.4-dlpyridineand acetic anhydride in the presence of pyridine according to the methodof Example l2.

EXAMPLE 23 Preparation of 2-( 3.5-dimethoxyphenyl)-5-(4-fluorophenyl)pentane A solution of 77 g. of 3-(4-fluorophenyl)propylbromide in 300ml. of ether was added dropwise over a 2 hour period to a refluxingsolution of g. of magnesium in 100 ml. of ether. The reaction mixturewas refluxed for an additional 30 minutes after the addition wascompleted. A solution of 68 g. of 3.5- dimethoxyacetophenone in 100 ml.of ether was then added dropwise to the reaction and the reactionmixture was refluxed for IV: hours. To the reaction was added 300 ml. ofa saturated ammonium chloride solution dropwise with stirring. Thelayers were separated and the aqueous layer extracted with ether. Theether extract was dried over magnesium sulfate and the ether removed invacuo to give an oil. An additional 1 1 L7 of3(4-fluorophenyl)propylbromide was worked up in EXAMPLE 24 Preparationof 2-( 3,5-dihydroxyphenyl )-5-(4-fluorophenyl) pentane Fifty grams ofthe above prepared 2-(3,5- dimethoxyphenyl)-5-(4-fluorophenyl)pentane,450 ml. of acetic acid and 180 ml. of 48pe'rcent HBr in water weremixed. While cooling. the mixture was saturated with hydrogen bromidegas (approximately one-half hour). The reaction was placed in an 87 bathand stirred for 17 hours. The reaction was then concentrated in vacuoand the residue neutralized with K CO and NaHCO extracted with ether,treated with charcoal and MgSO and filtered to yield 45 g. of 2-(3,5-dihydroxyphenyl )-5-( 4-fluorophenyl )pentane as a brown oil whichdistills at l/0.0l mmHg.

Analysis Calcd. for C H O F: C, 74.20; H, 6.98.

Found: C, 73.56; H, 7.04.

EXAMPLE 25 Preparation of 2-Benzyl-8-[ 5-( 4-fluorophenyl )-2-pentyl]- lO-hydroxy- 5-oxol .2.3.4-tetrahydro-5H-[ l ]benzopyrano[3.4- d]pyridenehydrochloride To 45 g. of 2-(3,5-dihydroxyphenyl) 5-(4-fluorophenyl)-pentane dissolved in I00 ml. of methanesulfonic acid wereadded in portions, 57 g. of l-benzyl-3-keto-4-carbethoxy piperidinehydrochloride. While stirring. 68 g. of POCl were added and the solutionwas stirred for 5 days at room temperature.

Water (300 ml.) and l80 ml. of CHCl were then added and the reactionmixture stirred for 30 minutes. After the addition of I00 ml. of 15percent NaOl-l, the reaction was stirred for an additional 10 minutes.The CHCl layer was separated and extracted with l0 percent HCI. The CHCllayer was concentrated and CH CN added thereto to yield 55 g. of thedesired product as the hydrochloride salt. m.p. 254-256C.

Analysis Calcd. for: C, 70.80; H, 6.14; Cl, 6.97; N, 2.75. Found: C,70.15; H, 6.17; Cl. 7.23; N, 2.74.

EXAMPLE 26 Preparation of Z-Benzyl-S.S-dimethyl-8-[S-(4-fluorophenyl)-2-pentyl l O-hydroxyl .2.3,4-tetrahydro- Sl-ll l ]benzopyrano[3.4-d]pyridine Sixty five grams of the above-prepared 2-Benzyl-8-[5-(4-fluorophenyl)-2-pentyll-IO-hydroxy-S-oxo- 1.2.3.4-tetrahydro-5H] l]benzopyrano[3.4-dlpyridine hydrochloride were suspended in 300 ml. ofCl-lCL After adding a Kl-lCO solution. the reaction was stirred for 30minutes. The chloroform layer was separated. dried over M380concentrated taken up in benzene and concentrated again. The concentratewas taken up in 185 ml. of hot anisole and the resulting solution wasadded dropwise to a solution of Cl-l MgBr in anisole (prepared by adding180 g. of cuasr in 500 ml. of ether to 40 g. of Mg in ml. of ether.evaporating the ether and adding 300 ml. of anisole). The reactionmixture was stored overnight at 62C. Water (200 ml.) was added slowly,followed by 400 ml. of 10 percent H SO The anisole was removed by steamdistillation and the resulting solid was taken up in chloroform,neutralized with KHCO dried over MgSO concentrated and the product (36.5g.), m.p. l88-l90C.. crystallized from CH CN.

EXAMPLE 27 5 ,5-Dimethyl-8-[ 5-( 4-fluorophenyl )-2-pentyl l O-hydroxy-5H-[ 1 ]benzopyrano[3,4-d ]pyridine EXAMPLE 28 5,5-Dimethyl-8-I5-phenyl-2-pentyl]- l O-hydroxy-SH- [l]benzopyrano[3,4-d1pyridine isprepared from 5,5-

I dimethyl-8-[5-phenyl-2-pentyl]-10-hydroxy-1,2.3.4-

tet'rahydro-5H-[ l ]benzopyrano[3,4-d]pyridine following the procedureof Example 27.

EXAMPLE 29 5,5-Dimethyl-8-( 3-methyl-2-octyl l O-[ 4-( piperidinobutyryloxy)-5H-[ 1]benzopyrano[3,4-d]pyridine hydrochloride N ocoaza -nCH3 RC1 CH3 ('31-lC1l(C11 on A mixture of 3.53 g. (0.01 mole) of5,5-dimethyl-lhydroxy-8-( 3-methyl-2-octyl)-5 H-[ 1]benzopyrano[3,4-d]-pyridine, 2.07 g. (0.01 mole) of'y-piperidinobutyric acid hydrochloride, 2.16 g. (0.0105 mole) ofN,N'-dicyclohexylcarbodiimide, and 160 ml. of dried methylene chloridewas stirred overnight at room temperature. The reaction mixture wascooled at approximately C. for several hours and was filtered to removedicyclohexylureas. The filtrate was evaporated in vacuo and the residuewas dissolved in 12.5 ml. of methylene chloride and 50 ml. ofcyclohexane. After standing overnight in the cold room (approximately5C.), the mixture was filtered again and the filtrate was evaporated invacuo. The residue was recrystallized from methylene chloride/ether,giving 4.1 g. of the product, m.p. 134l37.

Calcd. for: C H N O .HC1: C, 70.76; H, 8.72; N, 5.16. Found: C, 70.71;H, 8.91; N. 5.21.

EXAMPLE 30 5.5-Dimethyl-8-( l-pentyl)-10-[4-(piperidino)-butyryloxy]-5H-[ l ]benzopyrano[3,4-d]pyridine hydrochloride is preparedaccording to the method of Example 29 by reacting equimolar quantitiesof 5,5- dimethyll0-hydroxy-8-( l-pentyl)-5H-[1]benzopyrano[3,4-d]pyridine and y-piperidinobutyric acid hydrochloridein the presence of dicyclohexylcarbodiimide.

EXAMPLE 3] 5,5-Dimethyl-8-( 2-heptyl l 0-[4-(piperidino)butyryloxy]-5H-[ 1 ]benzopyrano[ 3,4- d]pyridinehydrochloride is prepared according to the method of Example 29 byreacting equimolar quantities of 5,5-dimethyl-8-(2-heptyl)-l0-hydroxy-5H[ 1 ]benzopyrano[ 3,4-d]pyridine and y-piperidinobutyric acidhydrochloride in the presence of dicyclohexyl carbodiimide.

EXAMPLE 32 5.5-Dimethyl-8-( l-cyclohexylethy1)-10-[4- (piperidino)butyryloxy]-5H-[ 1 ]benzopyrano[ 3.4- d]pyridine hydrochloride isprepared according to the method of Example 29 by reacting equimolarquantities of 5,5-dimethyl-l0-hydroxy-8-( l-cyclohexylethyl)- 5H[ 1]benzopyrano[3,4-d1pyridine and 'y-piperidinobutyric acid hydrochloridein the presence of dicyclohexyl carbodiimide.

EXAMPLE 33 5,5-Dimethyl-8-(3-cyclopropyl-2-propyl)-10-[4-(piperidino)-butyryloxy]-5H-[ 1 ]benzopyrano[3,4- dlpyridinehydrochloride is prepared according to the method of Example 29 byreacting equimolar quantities of5,5-dimethyl-10-hydroxy-8-(3-cyclopropyl-2- propyl)-5 H-[ l]benzopyrano[ 3,4-d1pyridine and y-piperidinobutyric acid hydrochloridein the presence of dicyclohexyl-carbodiimide.

EXAMPLE 34 5 ,5-Dimethyl-8-( Z-tetradecyl 1 0-1 4-( piperidinobutyryloxy]-5H-[ 1 ]benzopyrano[ 3,4-d]pyridine hydrochloride isprepared according to the method of Example 29 by reacting equimolarquantities of 5,5- dimethyl-10-hydroxy-8-(2-tetradecyl)-5H-[l]benzopyrano[3,4-d]pyridine and 'y-piperidinobutyric acidhydrochloridein the presence of dicyclohexyl carbodiimide.

EXAMPLE 35 5 ,5-Dimethyl-8-(2-eicosyl)-10-[4-(piperidino)-butyryloxy]-5H-[ l ]benzopyrano[ 3,4-d]pyridine hydrochloride isprepared according to the method of Example 29 by reacting equimolarquantities of 5,5- dimethyl-10-hydroxy-8-(2-eicosyl)-5H- 11 l]benzopyrano[ 3,4-d]pyridine and 'y-piperidinobutyric acid hydrochloridein the presence of dicyclohexyl carbodiimide.

EXAMPLE 36 5.5-Dimethyl-8-ethyl-lO-[4-(piperidino)- butyryloxy]-5H-[ l]benzopyrano[3.4-d]pyridine hydrochloride is prepared according to themethod of Example 29 by reacting equimolar quantities of 55-dimethyl-l-hydroxy-8-ethyl-5H-[ l ]benzopyrano[3,4- d]pyridine andy-piperidinobutyric acid hydrochloride in the presence of dicyclohexylcarbodiimide.

EXAMPLE 37 ,5-Dimethyl-8-methyll 0-[ 4-( piperidino butyryloxy]-5H-{ l]benzopyrano[3,4-d1pyridine hydrochloride is prepared according to themethod of Example 29 by reacting equimolar quantities of 5,5-dimethyl-l0-hydroxy-8-methyl-5H- [l ]benzopyrano[3,4-dlpyridine and'y-piperidinobutyric acid hydrochloride in the presence of dicyclohexylcarbodiimide.

EXAMPLE 38 5.5-Dimethyl-8-iso-propyl-l0-[4-(piperidino)-butyryloxy]-5H-[ l ]benzopyrano[ 3,4-d]pyridine hydrochloride isprepared according to the method of Example 29 by reacting equimolarquantities of 5,5- dimethyll O-hydroxy-8-iso-propyl-5H- [l ]benzopyrano[3 4-d]pyridine and y-piperidinobutyric acid hydrochloride in thepresence of dicyclohexyl carbodiimide.

EXAMPLE 39 5,5-Dimethyl-8-(2-hexyl)-l0-[4-(piperidino)- butyryloxy]-5H-[l]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to themethod of Example 29 by reacting equimolar quantities of 5,5-dimethyl-l0-hydroxy-8-(2-hexyl)-5H- [l]benzopyrano[3,4-d]pyridine andy-piperidinobutyric acid hydrochloride in the presence of dicyclohexylcarbodiimide.

EXAMPLE 40 5,5-Dimethyl-8-[5-phenyl-2-pentyl1-10-[4-(piperidino)-butyryloxy]-5H-[ l ]benzopyrano[3,4- d]pyridinehydrochloride is prepared according to the method of Example 29 byreacting equimolar quantities of5,5-dimethyl-l0-hydroxy-8-[5-phenyl-2-pentyl1- 5H-[ 1 ]benzopyrano[3,4-d]pyridine and y-piperidinobutyric acid hydrochloride in the presence ofdicyclohexyl carbodiimide.

EXAMPLE 41 5,5-Dimethyl-8-(3-methyl-2-octyl)-l0-[4- (morpholino)-butyryl0xy]-5H-[ 1 ]benzopyrano[3,4- d]pyridine hydrochloride isprepared according to the method of Example 29 by reacting equimolarquantities of 5,5-dimethyl-l0-hydroxy-8-(3-methyl-2-octyl)- 5H-[ 1]benzopyrano[3,4-d]pyridine and -y-morpholinobutyric acid hydrochloridein the presence of dicyclohexyl carbodiimide.

EXAMPLE 42 5,5-Dimethyl-8-( 3-methyl-2-octyl)- l O- [4- (pyrrolidino)butyryloxy]-5H-[ 1 ]benzopyrano[3,4 d]pyridine hydrochloride is preparedaccording to the method of Example 29 by reacting equimolar quantitiesof 5,5-dimethyl-l0-hydroxy-8-(3-methyl-2-octyl)- 5H-[ 1 ]benzopyrano[3,4-d1pyridine and y-pyrrolidinobutyric acid hydrochloride in thepresence of dicyclohexyl carbodiimide.

EXAMPLE 43 5,5-Dimethyl-8-(3-methyl-2-octyl)-10-[4-(2-methylpiperidino)butyryloxy1-5H- l ]benzopyrano[3,4-djpyridinehydrochloride is prepared according to the method of Example 29 byreacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[ 1 ]benzopyrano[3,4- d]pyridine andy-(2-methylpiperidino)butyric acid hydrochloride in the presence ofdicyclohexyl carbodiimide.

EXAMPLE 44 EXAMPLE 46 5 ,5-Dimethyl-8-( 3-methyl-2-octyl l 0-[ 3-(piperidino) propionyloxy1-5 H-[ l ]benzopyrano[ 3,4-

d]pyridine hydrochloride is prepared according to the method of Example29 by reacting equimolar quantities of5,5-dimethyl-lO-hydroxy-8-(3-methyl-2-octyl)- 5H-[ 1 ]benzopyrano[3,4-d1pyridine and B-piperidinopropionic acid in the presence ofdicyclohexyl carbodiimide'.

EXAMPLE 47 5 ,5-Dimethyl-8-( 3-methyl-2-octyl l 0- 4- (thiomorpholino)butyryloxy 1-5 H- [l]benzopyrano[3,4-d1pyridine hydrobromide isprepared according to the method of Example 29 by reacting equimolarquantities of 5,5-dimethyl- 10-hydroxy-8- (3-methyl-2-octyl)-5H-[ l]benzopyrano[ 3,4- d]pyridine and y-thiomorpholinobutyric acidhydrobromide in the presence of dicyclohexyl carbodiimide.

The compounds of this invention can also be prepared by the simultaneousdehydrogenation and debenzylation of the corresponding N-benzyl-l,2,3,4-tetrahydro-benzopyranopyridine as illustrated in the followingexample. The N-benzyl compound can be prepared according to the methoddescribed in US. Pat. No. 3,576,798.

5.5-Dimethyl-l0-ihydroxy-8-(3Qrnethyl-2-octyU-5H- l]benzopyrano[3,4-d]pyridine A mixture of 2.23 g. of2-benzyl-5,5-dimethyl-l0- hydroxy-8-( 3-methyl-2-octyl l,2,3,4-tetrahydro-5H- ll]benzopyrano[3,4-dlpyridine, 0.8 g. (10 percent)palladium on carbon, and I ml. of xylene was stirred and refluxed for 24hours. After removal of the catalyst, the filtrate was evaporated invacuo and the residue was recrystallized from acetonitrile; m.p.l54-l56.

The present invention includes within its scope, pharmaceuticalcompositions comprising, as an active in gredient, at least one of thecompounds of this invention in association with a pharmaceuticallyacceptable carrier or diluent. The compounds of this invention exhibitboth oral and parenteral activity and can be formulated in dosage formsfor oral, parenteral or rectal administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound is admixed with at least one inert diluent such as sucrose,lactose or starch. Such dosage forms can also comprise, as is normalpractice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate, and sweetening andflavoring agents. Tablets and pills can additionally be prepared withenteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such as water.Besides inert diluents, such compositions can also include adjuvants,such as wetting agents, emulsifying and suspending agents andsweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or nonaqueous solutions, suspensions oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil, andinjectable organic esters such as ester oleate. Such dosage forms mayalso contain adjuvants such as preserving, wetting, emulsifying anddispersing agents. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, by incorporating sterilizing agentsinto the compositions, by irradiating the compositions, or by heatingthe compositions. They can also be manufactured in the form of sterilesolid compositions which can be dissolved in sterile water, or someother sterile injectable medium immediately before use.

Compositions for rectal administration are suppositories which maycontain in addition to the active substance, excipients such as cocoabutter or a suppository wax.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient shall be such that a suitable dosage form is obtained. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration and on the duration of the treatment.

The following example further illustrates the pharmaceuticalcompositions which are a feature of this invention:

EXAMPLE 49 Tablets weighing 200 mg. and having the following compositionare prepared by standard tableting procedures:

wherein each R is lower alkyl, R, is lower alkanoyloxy and R is loweralkyl, cycloalkyl or ,5! i gm wherein Y is a straight or branched chainalkylene group having from 1 to carbon atoms and each R R and R are thesame or different members selected from the group consisting of hydrogenhalo, trifluoromethyl or loweralkyl.

2. A compound in accordance with claim 1, l0-acetoxy-5,5-dimethyl-8-(3-methyl-2-octyl)-5H- [l ]benzopyrano[3,4-d]pyridine.

3. A compound in accordance with claim 1 wherein R is lower alkanoyloxyand R is wherein Y is a straight or branched chain alkylene group havingfrom 1 to 10 carbon atoms and each R R and R are the same or differentmembers of the group consisting of hydrogen, halo, trifluoromethyl orloweralkyl.

1. A COMPOUND HAING FOLLOWING FORMULA
 2. A compound in accordance withclaim 1, 10-acetoxy-5,5-dimethyl-8-(3-methyl-2-octyl)-5H-(1)benzopyrano(3,4-d)pyridine.
 3. A compound in accordance with claim 1 wherein R3 islower alkanoyloxy and R2 is